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October 3, 2001
Northwestern Researcher Discovers Second Gene
for Lou Gehrig’s Disease
CHICAGO --- A second gene mutation that causes an
inherited form of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s
disease, has been identified by Teepu Siddique, M.D., the Northwestern
University researcher who, with collaborators from Massachusetts
General Hospital, discovered the first ALS gene (ALS1) in 1993.
ALS is a terminal, progressive neuromuscular disease that renders
the muscles of the body useless while leaving the mind unaffected.
There is currently no effective treatment or cure for ALS.
The newly identified gene mutation is responsible for a rare, slowly
progressive, early-onset form of the disease, called juvenile inherited
ALS (ALS2), discovered in highly inbred populations in North Africa
and the Middle East.
Siddique and colleagues discovered the gene, located on chromosome
2q33, in four Tunisian and Saudi Arabian families. They first identified
the location of the gene in 1994.
Siddique and an international consortium of researchers reported
the discovery of the aberrant gene in the Oct. 3 issue of Nature
Genetics.
Their findings also clarify why clinicians previously confused ALS2
for another neurodegenerative disease called juvenile primary lateral
sclerosis -- different mutations in the same gene are found in both
individuals with ALS2 and those with juvenile primary lateral sclerosis,
indicating that these conditions have a common genetic origin.
The accompanying editorial in the journal stated that the finding
by Siddique et al. represents an important advance in the field
of ALS research and in studies of neurodegeneration.
The gene for ALS2 is transmitted in an autosomal recessive pattern,
i.e., the individual inherits copies of the same recessive gene
from both parents. Symptoms of ALS2 manifest in the first or second
decade of life and progress slowly for 10 to 15 years, akin to those
of Stephen Hawking, the physicist.
In patients with the better known form of inherited ALS (ALS1),
symptoms generally occur age 40 to 50 and patients die within five
years. This form is autosomal dominant, that is, only one copy of
the gene is required to cause the disease.
In its normal form, the gene responsible for ALS2 codes for a substance
named alsin, a protein that plays an integral role in signaling
pathways, intracellular trafficking and the organization of the
cytoskeleton. Siddique and colleagues believe that, unlike ALS1,
which is caused by a novel new property in a mutated gene, called
a toxic gain of function, ALS2 results from loss of a physiologic
function.
This means that the protein’s functions can be predicted based
on its structure, thus providing an opportunity for direct examination
of the molecular consequence of the loss in model systems, Siddique
said.
"The predicted sequence of the alsin protein may indicate a
mechanism for motor-neuron degeneration because the predicted protein
motifs are exchanges of GTP [guanosine triphosphate, a compound
necessary for several important metabolic reactions] for small GTPase
proteins. These GTPases are involved in cell signaling, such as
transport of molecular cargo in cellular vesicles," Siddique
said.
"Elucidation of protein partners interacting with alsin may
inform us of basic mechanisms underlying neuronal degeneration.
Identification of crucial players in this pathway may serve as therapeutic
targets," Siddique said.
Siddique is the Abbott Laboratories Duane and Susan Burnham Research
Professor, professor of neurology and of cell and molecular biology,
director of the Les Turner ALS Foundation research and clinical
programs in the Herbert C. and Florence M. Wenske Neurological Research
Laboratories at Northwestern University Medical School and a member of the Northwestern
University Institute for Neuroscience.
Collaborating on this study were researchers from the Medical School,
as well as King Faisal Specialist Hospital and Research Center,
Riyadh, Saudi Arabia; Brown University, Providence, R.I.; King Fahad
Military Hospital, Jeddah, Saudi Arabia; Institute of Neurology,
Tunis, Tunisia; and Duke University Medical Center, Durham, N.C.
This study was funded by grants from the National
Institutes of Health, the Les Turner ALS Foundation, Grant Healthcare
Foundation, the Michael Jordan Foundation and the Ralph and Marian
Falk Medical Research Trust. Co-author Karim Ouahchi is a Muscular
Dystrophy Association-funded fellow, and co-author Wu-Yen Hung is
a Muriel Heller Fellow.
10/3/01
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